Multi-Layered Molecular Profiling Informs the Diagnosis and Targeted Therapy of Desmoplastic Small Round Cell Tumor

Desmoplastic small round cell tumor (DSRCT) is an ultra-rare sarcoma with limited treatment options. We performed whole-genome/exome, transcriptome, and DNA methylome analysis in 30 refractory DSRCT patients, complemented by (phospho)proteomic profiling in nine, within a nationwide precision oncology program. In eight patients (27%), DSRCT was diagnosed based on molecular profiling. Although all patients had “quiet” genomes, 28 (93%) received 107 molecular-based management recommendations, including assessment of clinical trial eligibility in 17 (57%). Nearly half of recommendations (45%) were based on overexpression of tyrosine kinases, as well as SSTR3/5 and CLDN6, detected in 33% and 20% of cases, respectively. Thirteen patients (46%) received recommended therapies, yielding disease control in eight (62%; partial response, n  = 5; stable disease, n  = 3), including three long-lasting responses (≥ 12 months) to pazopanib and trastuzumab deruxtecan, triggered by ERBB2 overexpression in the absence of constitutive ERBB2 signaling. Thus, multi-omics profiling enables individualized DSRCT treatment.